[보고서]장내 마이크로바이옴과 대사체의 관점에서 블랙라즈베리 유래 폴리페놀 추출물의 섭취가 쥐의 심혈관계 위험인자에 미치는 영향

황금택

장내 마이크로바이옴과 대사체의 관점에서 블랙라즈베리 유래 폴리페놀 추출물의 섭취가 쥐의 심혈관계 위험인자에 미치는 영향
Effects of Administration of Polyphenol-rich Extract from Black Raspberry on Risk Factors of Murine Cardiovascular System in Terms of Intestinal Microbiome and Metabolome 원문보기

보고서 정보
주관연구기관	서울대학교 Seoul National University
연구책임자	황금택
보고서유형	최종보고서
발행국가	대한민국
언어	한국어
발행년월	2020-09
과제시작연도	2020
주관부처	과학기술정보통신부 Ministry of Science and ICT
등록번호	TRKO202100014924
과제고유번호	1345317096
사업명	개인기초연구(교육부)(R&D)
DB 구축일자	2021-10-09
키워드	블랙라즈베리.심혈관계 건강.장내 마이크로바이옴.대사체.고콜린식이.담즙산.고콜레스테롤혈증.파이토케미칼.TMAO.

초록 ▼

□연구개요
Phytochemical의 섭취는 심혈관계 질환(cardiovascular disease, CVD) 위험 인자 완화에 도움을 주는 것으로 알려져 있다. 하지만 수많은 선행 연구들은 이러한 효과를 phytochemical이 가진 항산화나 항염증 효과 또는 유전자 조절의 관점에서 설명하였다. 본 연구팀은 블랙라즈베리 유래 phytochemical이 체내 흡수율이 낮고, 장내에 축적된다는 선행 연구를 기반으로 phytochemical의 CVD 완화 효과는 장내 microbiota의 생장 환경 변화와 metabolite 조성의 변화에 좀 더 기인할 것이라는 가설을 세웠다. 따라서 본 연구의 최종 목표는 블랙라즈베리 유래 폴리페놀의 섭취가 CVD 위험 인자에 미치는 영향을 장내 마이크로바이옴과 대사체의 관점에서 확인하는 것이다.

□연구 목표대비 연구결과
· 고콜린식수 또는 고TMAO식수의 섭취
- CVD 위험 증가: 혈중 총콜레스테롤, LDL-콜레스테롤 증가, 대동맥 intima-media thickness 증가, 장내 TMA 농도 및 혈중 TMAO 농도 증가
- 장내마이크로바이옴 변화: genus Allobaculum, order Clostridiales, order YS2등 증가, 알파다양성(observed OTUs, Shannon index) 감소, 장내 총 담즙산 함량 감소, 혈중 담즙산 조성 변화(일차담즙산 CA, CDCA 등 감소, 이차담즙산 LCA 증가)
- 간 조직 내 Ldlr, Srebf2 유전자 발현량 증가
· 식이 중 블랙라즈베리의 첨가
- CVD 위험 완화: 혈중 총콜레스테롤, LDL-콜레스테롤 감소, 대동맥 intima-media thickness 감소, 장내 TMA 농도 및 혈중 TMAO 농도 감소
- 장내마이크로바이옴 변화: family Bacillaceae, genus Anaerohabdus, genus Mucispirillum 등 증가, 알파다양성(observed OTUs, Shannon index) 증가, 장내 총 담즙산 함량 증가, 혈중 담즙산 조성 변화(일차담즙산 CA, CDCA 등 감소, 이차담즙산 LCA 증가)
- 간 조직 내 Ldlr, Srebf2 유전자 발현량 증가

□연구개발결과의 중요성
- 블랙라즈베리 유래 폴리페놀의 장기간 섭취가 식이로 장내 마이크로바이옴 변화를 유도한 쥐의 마이크로바이옴, 혈중 콜레스테롤, 담즙산 조성, 콜레스테롤과 담즙산 대사조절 유전자의 발현량에 미치는 영향을 시스템적인 측면에서 확인함
- 본 연구 결과는 파이토케미컬의 CVD 완화 효과가 물질 자체의 생리활성에 의한 것 이외에도 장내 마이크로바이옴, 메타볼롬, 콜레스테롤과 담즙산 대사 등의 종합적 조절에 의한 작용이라는 가설의 근거로 활용 가능
- 블랙라즈베리를 프리바이오틱스와 같은 자원으로 활용할 수 있는 가능성을 확인하였고, 특히 CVD 위험을 높인 동물 모델에서 그 가치와 기전을 시스템적인 측면에서 밝혀낸 연구이기 때문에 소재에 고부가가치 부여

(출처 : 요 약 문 2p)

목차 Contents

표지 ... 1연구결과 요약문 ... 2목차 ... 31. 연구개발과제의 개요 ... 3 1.1 연구의 필요성 ... 3 1.2 연구의 가설 ... 4 1.3 연구의 최종목표 ... 4 1.4 연구범위 ... 52. 연구수행내용 및 연구결과 ... 6 2.1 연구방법 ... 6 2.2 연구수행내용 및 연구결과 ... 153. 연구개발결과의 중요성 ... 444. 참고문헌 ... 445. 연구성과 ... 46끝페이지 ... 48

표/그림 (49)

표 Graphical abstract of this study
표 Polyphenol-rich extracts from black raspberry might alleviate cardivascular risk via changes in intestinal microbiome and metabolome related to choline metabolism. Purple lines: possible pathways which inhibit atherosclerotic process
표 Total polyphenols in black raspberry lyophilized powder. Bars represent means and standard deviations (n=3)
표 Anthocyanin composition of black raspberry extract prepared by 80% (v/v) ethanol solution
표 Experimental design of Study 1
표 Composition of experimental diets
표 Experimental design of Study 2
표 Quality score plot of each sequence base in forward and reverse reads
표 Multiple reaction monitoring conditions for each phenolic acid
표 Primer sequences for analysis of genes related to cholesterol and bile acid metabolism in rats
표 Body weight and daily diet and water intakes of the rats fed experimental diets
표 Serum concentrations of (A) choline and (B) trimethylamine-N-oxide (TMAO) in female SD rats. ns, not significant. Plots with different letters are significantly different
표 Microscopic analysis of the hematoxylin and eosin-stained aorta sections of female SD rats (×400 magnification)
표 Effects of choline on serum levels of glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), total cholesterol, and high density lipoprotein (HDL)-cholesterol in female SD rats
표 Body weights and intakes of diet and water of the rats
표 Serum triglycerides (A), total cholesterol (B), HDL-cholesterol (C), and LDL-cholesterol (D) in Sprague-Dawley rats. All data represent the means and standard deviations (n=7-8). Different small letters indicate significant differences among the groups (p<0.05; one-way ANOVA and Duncan’s multiple range test)
표 Microscopic analysis of the hematoxylin and eosin-stained aorta sections of female SD rats (×100 magnification)
표 Effect of excessive choline intake on choline-derived metabolites in Sprague-Dawley rats. (A) Choline, trimethylamine (TMA), and trimethylamine-N-oxide (TMAO) in cecal content of the rats. (B) Serum TMAO level in the rats. Values represent means and standard deviations (n=10). *n=5. Different small letters indicate significant differences among the groups (p<0.05; one-way ANOVA and Duncan´s multiple range test)
표 Relative mRNA level of genes involved in pro- and anti-inflammation in the liver of Sprague-Dawley rats. All the relative expressions of genes were normalized to glyceraldehyde-3-phosphate dehydrogenase expression. All data represent the means and standard deviations (n=7-8). Different small letters indicate significant differences among the groups (p<0.05; one-way ANOVA and Duncan’s multiple range test)
표 Relative mRNA levels involved in pro- and anti-inflammation in the adipose tissue of Sprague-Dawley rats. All the relative expressions of genes were normalized to glyceraldehyde-3-phosphate dehydrogenase expression. All data represent the means and standard deviations (n=4-6). Different small letters indicate significant differences among the groups (p<0.05; one-way ANOVA with Duncan’s multiple range test or Kruskal-Wallis test with Mann-Whitney U test)
표 Protein expressions of NF-κB (A and C), I-κB (A and D), and COX-2 (B and E) in the liver of Sprague-Dawley rats. All data represent the means and standard deviations (n=6-8). Different small letters indicate significant differences among the groups (p<0.05; one-way ANOVA and Duncan’s multiple range test)
표 Rarefaction curves of observed OTUs (operational taxonomic units) from cecal contents of female SD rats
표 Distribution of α-diversity within groups by Shannon index
표 Principal coordinate analysis plots of beta-diversity (unweighted UniFrac) in feces and cecal content
표 Comparison of bacterial relative abundance in feces between HFC and HFCB by LEfSe analysis. Only taxa meeting an LDA threshold of >2 are shown
표 Comparison of bacterial relative abundance in cecal content between HF and HFC by LEfSe analysis. Only taxa meeting an LDA threshold of >2 are shown
표 Comparison of bacterial relative abundance in cecal content between HFC and HFCB by LEfSe analysis. Only taxa meeting an LDA threshold of >2 are shown
표 Unconjugated (A) and conjugated (B) bile acids in cecal content of the female SD rats. Bar represents mean ± standard deviation. Statistically significant differences were assessed by Kruskal-Wallis test and Mann-Whitney U test (*p<0.05 and **p<0.01)
표 Summary of bile acid profile in cecal content of the female SD rats. BAs, bile acids. 2nd, secondary bile acids. 1st, primary bile acids. Bar represents mean ± standard deviation. Statistically significant differences were assessed by Kruskal-Wallis test and Mann-Whitney U test (*p<0.05 and **p<0.01)
표 Unconjugated (A) and conjugated (B) bile acids in serum of the female SD rats. Bar represents mean ± standard deviation. Statistically significant differences were assessed by Kruskal-Wallis test and Mann-Whitney U test (*p<0.05 and **p<0.01)
표 Summary of bile acid profile in serum of the female SD rats. BAs, bile acids. 2nd, secondary bile acids. 1st, primary bile acids. Bar represents mean ± standard deviation. Statistically significant differences were assessed by Kruskal-Wallis test and Mann-Whitney U test (*p<0.05 and **p<0.01)
표 Short chain fatty acids in cecal content of the female SD rats. Bar represents mean ± standard deviation. Bars with different letters are significantly different (p<0.05 by one-way ANOVA and Duncan’s multiple range test)
표 Hepatic mRNA expression of genes responsible for cholesterol and bile acid metabolism in the female SD rats. Relative gene expression was normalized to Gapdh. Bar represents mean ± standard deviation, Bars with different letters within the same genes are significantly different (p<0.05 by one-way ANOVA and Duncan´s multiple range test)
표 Protein expressions of CYP7A1 (A and B) in the liver of SD rats. All data represent the means and standard deviations (n=8-9). Different small letters indicate significant differences among the groups (p<0.05; one-way ANOVA and Duncan’s multiple range test)
표 Effect of trimethylamine-N-oxide (TMAO) intake on serum TMAO level in SD rats. Values represent means and standard deviations (n=4). Different small letters indicate significant differences among the groups (p<0.05; one-way ANOVA and Duncan´s multiple range test)
표 Effects of trimethylamine-N-oxide (TMAO) intake on serum levels of total cholesterol, glutamic oxaloacetic transaminase (GOT), and glutamic pyruvic transaminase (GPT). Values represent means and standard deviations (n=4). Different small letters indicate significant differences among the groups (p<0.05; one-way ANOVA and Duncan´s multiple range test)
표 Body weights and intakes of diet and water of the rats
표 Serum triglycerides (A), total cholesterol (B), HDL-cholesterol (C), and LDL-cholesterol (D) in SD rats. All data represent the means and standard deviations (n=8-9). Different small letters indicate significant differences among the groups (p<0.05; one-way ANOVA and Duncan’s multiple range test)
표 Effect of intakes of trimethylamine-N-oxide (TMAO) and black raspberry polyphenol-rich extract on serum TMAO level in Sprague-Dawley rats. Values represent means and standard deviations (n=10). Different small letters indicate significant differences among the groups (p<0.05; one-way ANOVA and Duncan´s multiple range test)
표 Rarefaction curves of observed OTUs (operational taxonomic units) from cecal contents of female SD rats
표 Distribution of α-diversity within groups by Shannon index
표 Principal coordinate analysis plots of beta-diversity (unweighted UniFrac) in cecal content
표 Comparison of bacterial relative abundance in feces between HFC and HFCB by LEfSe analysis. Only taxa meeting an LDA threshold of >2 are shown
표 Unconjugated (A) and conjugated (B) bile acids in cecal content of the female SD rats. Bar represents mean ± standard deviation. Statistically significant differences were assessed by Kruskal-Wallis test and Mann-Whitney U test (*p<0.05,**p<0.01, and ***p<0.001)
표 Summary of bile acid profile in cecal content of the female SD rats. BAs, bile acids. 2nd, secondary bile acids. 1st, primary bile acids. Bar represents mean ± standard deviation. Statistically significant differences were assessed by Kruskal-Wallis test and Mann-Whitney U test (*p<0.05,**p<0.01, and ***p<0.001)
표 Unconjugated (A) and conjugated (B) bile acids in serum of the female SD rats. Bar represents mean ± standard deviation. Statistically significant differences were assessed by Kruskal-Wallis test and Mann-Whitney U test (*p<0.05,**p<0.01, and ***p<0.001)
표 Summary of bile acid profile in serum of the female SD rats. BAs, bile acids. 2nd, secondary bile acids. 1st, primary bile acids. Bar represents mean ± standard deviation. Statistically significant differences were assessed by Kruskal-Wallis test and Mann-Whitney U test (*p<0.05 and **p<0.01)
표 Short chain fatty acids in cecal content of the female SD rats. Bar represents mean ± standard deviation. Bars with different letters are significantly different (p<0.05 by one-way ANOVA and Duncan’s multiple range test)
표 Hepatic mRNA expression of genes responsible for cholesterol and bile acid metabolism in the female SD rats. Relative gene expression was normalized to Gapdh. Bar represents mean ± standard deviation, Bars with different letters within the same genes are significantly different (p<0.05 by one-way ANOVA and Duncan's multiple range test)

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